Antiviral treatment CFS herpesvirus patients -Subset-directed-Lerner

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Subset-directed antiviral

treatment of 142 herpesvirus

patients with CFS

This article was published in the following Dove Press

Journal:

Virus Adaptation and Tretment,

24 May 2020

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Authors

A Lerner1

Safedin Beqaj2

T Fitzgerald3

Ken Gill4

Carol Gill4

Edington4

1Department of Medicine,

Beaumont Hospital, Royal Oak;

2Wayne State University School of

Medicine, Detroit; 3Department

of Medical Education, University

of Michigan Medical School, Ann

Arbor, Michigan; 4The Dr A

Lerner Chronic Fatigue Syndrome

Foundation, Beverly Hills, Michigan,

USA

Correspondence: A Lerner

32804 Pierce Road, Beverly Hills,

MI 48025, USA

Tel +1

Fax +1

Email amartinlerner@...

ABSTRACT

Purpose:

We hypothesized that chronic fatigue syndrome (CFS) may be

caused by single or multiple Epstein–Barr virus (EBV),

cytomegalovirus (HCMV), or human herpesvirus 6 (HHV6)

infection.

To determine if CFS life-altering fatigue and associated findings

including muscle aches, tachycardia at rest, chest aches, left

ventricular dysfunction, syncope, and elevated herpesvirus

serum antibody titers are reversed by long-term subset-directed

valacyclovir and/or valganciclovir.

Patients and methods:

Data were collected at physician visits every 4–6 weeks from

142 CFS patients at one clinic from 2001 to 2007. To be

included in this study, patients had to be followed for at least six

months.

The data captured included over 7000 patient visits and over

35,000 fields of information. Severity of fatigue was monitored

by a validated Energy Index Point Score® (EIPS®).

Baseline and follow-up serum antibody titers to EBV, HCMV,

and HHV6, as well as coinfections with Borrelia burgdorferi,

Anaplasma phagocytophila, Babesia microti, and

antistreptolysin O, 24-hour ECG Holter monitors, 2D

echocardiograms, cardiac dynamic studies, symptoms, and

toxicity were captured and monitored. International criteria for

CFS plus a specifically designed CFS diagnostic panel were

used.

Results and conclusions:

The Group A herpesvirus CFS patients (no coinfections)

returned to a near-normal to normal life (P = 0.0001).

The long-term EIPS value increased (primary endpoint, P ,

0.0001) with subset-directed long-term valacyclovir and/or

valganciclovir therapy.

Secondary endpoints (cardiac, immunologic, and neurocognitive

abnormalities) improved or disappeared.

Group B CFS patients (herpesvirus plus coinfections) continued

to have CFS.

Keywords: valacyclovir, valganciclovir, treatment, chronic fatigue

syndrome, CFS, Energy Index Point Score®, EIPS®

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Introduction

Chronic fatigue syndrome (CFS) is a life-altering illness affecting

women to men in a ratio of 4:1,1–3 for which there is no

evidence-based etiology or treatment.4–7

An association of CFS with an infectious gamma retrovirus

XMRV, previously found in high-grade malignant prostate

cancers, has been reported.8

This xenotropic virus is similar to Maloney murine leukemia and

the sarcoma virus in rodent, feline, and primate species. XMRV

possesses a slow mechanism for oncogenesis, and its course

does not always lead to cancer.8,9

However, the XMRV report requires confirmation.10

Cardiac, immunologic, radiographic, and genetic abnormalities

are present in CFS patients.11–21 We hypothesized that CFS

is caused by Epstein–Barr virus (EBV), cytomegalovirus

(HCMV), and human herpesvirus 6 (HHV6) in single or multiple

virus infection.22

This suggests CFS patients continue EBV, HCMV, and HHV6

herpesvirus replication, and do not achieve the viral latency

necessary for recovery.23–25

We propose that early and middle herpesvirus (EBV, HCMV,

HHV6) gene products to about the fiftieth gene of these complex

viruses, containing over 200 openreading frames, are

synthesized without achieving complete virus formation.26

We now test this hypothesis with the nucleosides valacyclovir for

a suspected EBV CFS subset and valganciclovir for suspected

HCMV or HHV6 CFS subsets.

We report long-term benefit, assessed by the validated severity

of an illness metric, the Energy Index Point Score® (EIPS®).27

Seventy-nine of 106 (74.5%) CFS patients returned to a

near-normal to normal life (primary endpoint). Secondary

endpoints of cardiac, immunologic, and neurocognitive

abnormalities improved or disappeared.

The data support the paradigm that CFS illness is a herpesvirus

infection.

Group A CFS patients have EBV, HCMV, and HHV6 in single or

multiple infection without coinfection.

Group B CFS patients are similar to Group A, but with

coinfections, tick-borne Borrelia burgdorferi, Babesia microti,

Anaplasma phagocytophila, and/or adult rheumatic fever.

Our research questions were whether subset-directed antiviral

therapy to single and multiple herpesvirus CFS patient groups

causes a significant change in EIPS; what percentages of

groups A and B CFS patients have EBV, HCMV, and/or HHV6

infection; whether long-term valacyclovir (for EBV) and

valganciclovir (for HCMV, HHV6) treatment can cause lasting

improvement in EIPS values for CFS patients; if long-term

valacyclovir and/or valganciclovir are free of deleterious effects

to complete blood count (CBC), aspartate aminotransferase

(AST), alanine aminotransferase (ALT), and creatinine; whether

single and coinfection CFS subsets respond similarly; and if

there are identifiable demographics of Group A CFS patients

who are " responders " and " nonresponders " to antiviral therapy?

```

Discussion

We describe a CFS illness exemplifying a conflict between a

complex system and attempts at reductionism.38 CFS illness is

divided into Group A herpesvirus (EBV, HCMV, HHV6) without

coinfection and Group B herpesvirus CFS with coinfection(s).

Coinfections are, remarkably tick-borne Lyme disease,

babesiosis and anaplasmosis, as well as non-tick-borne adult

rheumatic fever.

Long-term valacyclovir and/or valganciclovir subset-directed

administration improved or eliminated CFS symptoms in Group

A CFS patients, allowing them to return to normal life.

EBV, HCMV, and HHV6 single and multiple herpesvirus Group

A CFS patients were identified and responded equally well.

Different patient populations in other CFS clinics may have

varying percentages of these three herpesviruses. Valacyclovir

and valganciclovir as administered here were safe.

Single and multiple infected Group A CFS patients responded.

An initial Jarisch-Herxheimer response at the start of antiviral

medication initiates successful treatment.

The higher the baseline EIPS, the better the prognosis. The

long-term recovery of Group A CFS patients reported in this

study is unprecedented.

These remarkable results are dependent upon the careful

diagnostic panel outlined here under Methods. We emphasize

that the serologic antigens utilized for antibody assays of B.

burgdorferi are identical to those used by the US Centers for

Disease Control.

It is unclear whether XMRV gamma retrovirus infection initiates

the immunosuppression which may be responsible for CFS.

Nevertheless, specific herpesvirus antiviral treatment reversed

CFS illness in 79 of 106 Group A CFS patients.

Earlier studies suggesting a herpesvirus CFS causation had not

used either the diagnostic criteria or long-term herpesvirus

therapy, nor had previous herpesvirus CFS research separated

groups A and B CFS which is critical to these results.4,5

Cardiac muscle disease, syncope, chest pain, positive tilt table

tests, tachycardias at rest, decreased left ventricular ejection

fraction, and left ventricular dilatation improved and/ or

disappeared with antiviral treatment. The abnormal HM is a

reliable biomarker of CFS cardiac disease. The EIPS is integral

to follow severity and reversal of CFS illness.

Questions about the pathogenesis of CFS remain. There is a

preponderance of tick-borne B. burgdorferi, and Anaplasma and

Babesia coinfections in Group B CFS patients.

Studies of possible antibiotics in patients with suspected

chronic Lyme disease need to consider the possibility of an

unrecognized presence of Group B herpesvirus CFS.

Does herpesvirus CFS inhibit a class-switch transformation from

IgM to IgG in B. burgdorferi infection? Elevated IgG HCMV titers

with no IgM HCMV titers are common in human

immunodeficiency virus (HIV)-acquired immunodeficiency

syndrome (AIDS) patients, but AIDS patients have HCMV DNA

in their blood by polymerase chain reaction.

Does nonpermissive latent herpesvirus replication in CFS inhibit

classic IgM/IgG class-switch interchange for the involved CFS

herpesvirus?

Meta-analysis of multiple randomized CFS therapeutic studies

have determined a 17% placebo response.39 Graded exercise

and psychotherapy alleviate some CFS symptoms,6,7 but

neither therapy approaches the results of this report.

The data here suggest exercise may be tolerated at EIPS > 7.

A CFS patient (EIPS value > 5) with a posttreatment EIPS value

of 6 lives a normal life with only a short midday nap. The present

data are remarkable considering that these CFS patients had

been ill for a mean of 4.8 years before antiviral therapy was

begun. The mean duration of antiviral therapy for Group A CFS

patients was 2.4 years. Both valacyclovir and valganciclovir were

equally effective in single or multiple herpesvirus CFS subsets.

In these CFS patients, herpesvirus antigenemia, viremia, and

polymerase chain reactions in CFS tissues and bloods were

negative.4,15 The CFS nonpermissive abortive herpesvirus

paradigm postulates mRNA to middle or late EBV, HCMV, and

HHV6 genes is present in the blood macrophages and

lymphocytes of CFS patients.

The presence of IgM serum antibodies to the nonstructural

tegument middle-gene products HCMV p52 and HCMV CM2 in

HCMV CFS is consistent with this hypothesis.24,25 CFS is a

result of persistent single or multiple EBV, HCMV and/or HHV6

infections(s), categorized as a two-group complex illness without

coinfection (Group A) or with coinfections (Group .

These data show that 74.5% of 106 Group A CFS patients

returned to near-normal to normal lives after long-term

herpesvirus subset-directed antiviral therapy.

Finally, the rationale for prolonged antiviral treatment requires

discussion. This CFS herpesvirus paradigm is that

herpesviruses (EBV, HCMV, HHV6) are constantly attempting to

produce virulent complete virus as early, middle, and late gene

product in progression, and, ultimately, cytopathic effects, and

an inflammatory cytolysis of the affected cells.

Progeny-complete herpesvirus then continues to infect new host

cells. Similarly, the host-immune system attempts to inhibit

herpesvirus replication and induce silent virus latency as

intranuclear episomes with no viral gene products.

In CFS, we hypothesize there is immediate-early gene and early

gene expression, dysregulation of host cell functions, and cell

cycle progression leading ultimately to noninflammatory

apoptosis, such as that observed at cardiac biopsy.15

This proposed CFS process produces no viral DNA, no viral

antigenemia, and no virion maturation.40 The CFS patient

cannot successfully achieve herpesvirus latency.

Valacyclovir (EBV) and valganciclovir (HCMV, HHV6) inhibit

viral DNA polymerases. The long duration of antiviral therapy

responds to the ongoing opposing forces, ie, virus

induction-infected cellular destruction versus cellular survival by

an effective immune response.

We continue valacyclovir/valganciclovir until the EIPS is >7. If no

further antiviral therapy is necessary, the CFS patient now

independently maintains herpesvirus latency.

The biologic parameters to be followed in this ongoing process

are critical in our diagnostic panel and are described fully under

Methods.

These are EBV VCA, IgM (returns to negative), EBV, EA-D

(decreases and returns to negative), HCMV IgM p52 and IgM

CM2 (return to normal), and HM abnormalities (eg, T-waves

normalize and tachycardias disappear).

This thesis predicts that mRNA to intermediateearly herpesvirus

genes is circulating in mononuclear cells in the blood of CFS

patients, but this mRNA is not present in healthy subjects.